cancers

Review Prospects for Using Expression Patterns of Paramyxovirus Receptors as Biomarkers for Oncolytic Virotherapy

Olga V. Matveeva 1,* and Svetlana A. Shabalina 2,*

1 Sendai Viralytics LLC, 23 Nylander Way, Acton, MA 01720, USA 2 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA * Correspondence: [email protected] (O.V.M.); [email protected] (S.A.S.)

 Received: 27 October 2020; Accepted: 1 December 2020; Published: 5 December 2020 

Simple Summary: Some non-pathogenic viruses that do not cause serious illness in humans can efficiently target and kill cancer cells and may be considered candidates for cancer treatment with virotherapy. However, many cancer cells are protected from viruses. An important goal of personalized cancer treatment is to identify viruses that can kill a certain type of cancer cells. To this end, researchers investigate expression patterns of cell entry receptors, which viruses use to bind to and enter host cells. We summarized and analyzed the receptor expression patterns of two paramyxoviruses: The non-pathogenic measles and the Sendai viruses. The receptors for these viruses are different and can be or with attached carbohydrates. This review discusses the prospects for using these paramyxovirus receptors as biomarkers for successful personalized virotherapy for certain types of cancer.

Abstract: The effectiveness of oncolytic virotherapy in cancer treatment depends on several factors, including successful virus delivery to the tumor, ability of the virus to enter the target malignant cell, virus replication, and the release of progeny virions from infected cells. The multi-stage process is influenced by the efficiency with which the virus enters host cells via specific receptors. This review describes natural and artificial receptors for two oncolytic paramyxoviruses, nonpathogenic measles, and Sendai viruses. Cell entry receptors are proteins for measles virus (MV) and sialylated (sialylated or /) for Sendai virus (SeV). Accumulated published data reviewed here show different levels of expression of cell surface receptors for both viruses in different malignancies. Patients whose tumor cells have low or no expression of receptors for a specific oncolytic virus cannot be successfully treated with the virus. Recent published studies have revealed that an expression signature for immune is another important factor that determines the vulnerability of tumor cells to viral infection. In the future, a combination of expression signatures of immune and receptor genes could be used to find a set of oncolytic viruses that are more effective for specific malignancies.

Keywords: oncolytic viruses; oncolytic virotherapy; viral oncolysis; measles virus; Sendai virus; biomarkers; virus receptors; receptor retargeting; virus receptor expression; receptors; receptors; gangliosides

1. Introduction Oncolytic viruses are promising new agents for cancer treatment. They can kill cancer cells directly through infection or indirectly through activation of the immune system [1,2]. For the most effective

Cancers 2020, 12, 3659; doi:10.3390/cancers12123659 www.mdpi.com/journal/cancers Cancers 2020, 12, 3659 2 of 28 virotherapy, elimination of malignant cells with a combination of both direct and indirect destruction is desirable. Like all viruses, oncolytic viruses use specific receptors to bind to and enter host cells. This review describes the tendency of tumor cells to overexpress certain viral receptors, but it also Cancers 2020, 12, x 2 of 27 shows that, to varying degrees, these receptors are also expressed in many normal cells. However, regardlessdestruction of whether is desirable. cells areLike normal all viruses, or malignant, oncolytic viruses absence use of specific receptors receptors for a to particular bind to and virus enter makes the cellshost resistantcells. This to review this virus describes infection. the tendency So, for of better tumor identification cells to overexpress of individual certain viral patients receptors, who are mostbut likely it also tobenefit shows that from, to virotherapy, varying degrees, their these tumor receptors cells should are also be expressed screened in for many the presencenormal cells. of virus receptors.However, For manyregardless oncolytic of whether viruses, cells suchare normal receptors or malignant, are well characterized.absence of receptors Thus, for simple a particular tests that evaluatevirus protein makes the or RNAcells resistant levels in to tumor this virus tissue infection. could So, provide for better information identification about of individual expression patients levels of a who are most likely to benefit from virotherapy, their tumor cells should be screened for the presence virus receptor. of virus receptors. For many oncolytic viruses, such receptors are well characterized. Thus, simple Receptor mediated virus entry into a cell is only the first step in viral infection. Next, the virus tests that evaluate protein or RNA levels in tumor tissue could provide information about expression mustlevels break of through a virus receptor. the cellular antiviral defense system, which usually effectively protects normal cells fromReceptor any virus mediated infection. virus Key entry players into a cell in such is only protection the first step are in interferons viral infection. (IFNs); Next they, the helpvirus cells detectmust the presencebreak through of a virusthe cellular and, inantiviral response, defense restrict system proliferation,, which usually slow effectively down metabolic protects normal processes, and triggercells from any virus [3 infection.,4]. However, Key players malignant in such cells protection frequently are interferons have dysfunctional (IFNs); they IFN help pathways. cells Suchdetect dysfunction the presence helps of them a virus to evadeand, in theresponse, immune restrict system proliferation, and survive, slow thus down promoting metabolic tumorprocesses growth., The sameand t IFNrigger defects apoptosis that [3,4] help. However, cancer cells malignant escape immunecells frequently surveillance have dysfunctional make them vulnerableIFN pathways to. virus infectionSuch [ 5 dysfunction]. Nevertheless, helps not them all malignantto evade the cells immune have dysfunctional system and survive IFN pathways., thus promot Someing oftumor them can growth. The same IFN defects that help cancer cells escape immune surveillance make them produce and/or respond to IFN signals and protect themselves from a virus infection. So, theoretically, vulnerable to virus infection [5]. Nevertheless, not all malignant cells have dysfunctional IFN evenpathways. if a cancer Some cell hadof them receptors can produce for a particular and/or respond oncolytic to IFN virus signals it still and could protect be themselves resistant tofrom infection a by thevirus virus. infection. So, theoretically, even if a cancer cell had receptors for a particular oncolytic virus it Somestill could viruses be resistant require to cells infection to express by the processing virus. enzymes that modify or cleave the viral proteins necessaryS forome the viruses formation require ofcells mature to express infectious processing virions. enzymes Thus, that modif fusiony or protein cleave inthe paramyxoviruses viral proteins is synthesizednecessary for as anthe inactiveformation precursor of mature andinfectiou is activateds virions. throughThus, fusion proteolytic protein in cleavage paramyxoviruses by the cellular is protease.synthesized Without as such an inactive cleavage precursor the virus and isunable is activated to sustain through infection. proteolytic For MV,cleavage this activatingby the cellular protease is furinprotease. [6] and Without for SeV such it can cleavage be a numberthe virus of is serineunable proteases to sustain (TPSB2infection [. 7For–9], MV PRSS1, this [ activating10], PLG [11], F10 [12prote], andase is TMPRSS2 furin [6] and [13 for]). SeV Some it can of be these a number proteases of serine are proteases overexpressed (TPSB2 [7– in9],cancer PRSS1 [10] cells, PLG [14 –16]. [11], F10 [12], and TMPRSS2 [13]). Some of these proteases are overexpressed in cancer cells [14–16]. In addition to those listed, the expression levels of other host genes influence vulnerability of cancer In addition to those listed, the expression levels of other host genes influence vulnerability of cancer cellscells to a virusto a virus infection. infection. Figure Figure1 illustrates 1 illustrates factors factors necessary necessary for for a a cell cell to to become become vulnerable vulnerable to to paramyxovirusparamyxovirus infection. infection.

FigureFigure 1. Factors 1. Factors influencing influencing cells’ cells’vulnerability vulnerability to to paramyxovirus paramyxovirus infection. infection. The host The cell host needs cell to needs (1) to (1) expressexpress virus virus receptors receptors (2)(2) havehave a malfunctioning malfunctioning IFN IFN pathway, pathway, (3) (3) express express proteases proteases responsible responsible for for proteolyticproteolytic activation activation of virus of fusion virus fusion rotein, rotein and (4), and have (4) other have genes other that genes require that further require identification. further identification. Cancers 2020, 12, 3659 3 of 28

Cancers 2020, 12, x 3 of 27 To predict if a patient is likely to respond to oncolytic virotherapy, testing for the presence of virus receptorsTo in predict tumor tissueif a patient is not is sulikelyfficient. to respond Additional to oncolytic tests arevirotherapy, also needed testing to for reveal the presence the presence of of impairedvirus IFNreceptors signaling in tumor in thetissue patient’s is not sufficient. cancer cells,Additional and the tests expression are also needed of virus to reveal processing the presence enzymes and yetof impaired to be identified IFN signaling other proteinsin the patient’s that accommodate cancer cells, and virus the infection. expression Currently, of virus processing such tests are commerciallyenzymes and unavailable yet to be andidentified need other to be developedproteins that to accommodate optimize patient virus selectioninfection. protocolsCurrently, forsuch future clinicaltests trials. are commercially unavailable and need to be developed to optimize patient selection protocols Oncolyticfor future clinical paramyxoviruses trials. might become powerful anticancer agents [17–19]. Figure2 shows Oncolytic paramyxoviruses might become powerful anticancer agents [17–19]. Figure 2 shows the life cycle of the viruses, which can trigger syncytium (a polykarion) formation that protects virions the life cycle of the viruses, which can trigger syncytium (a polykarion) formation that protects virions fromfrom host host neutralizing neutralizing antibodies antibodies during during intratumor intratumor virus repl replicationication and and spreading. spreading.

FigureFigure 2. A 2. visual A visual representation representation of of the the cell cell cyclecycle of measles virus virus (MV) (MV) and and Sendai Sendai virus virus (SeV) (SeV).. Both Both virusesviruses belong belong to theto theParamyxoviridae Paramyxoviridaefamily, family, butbut MV belongs belongs to to the the MorbillivirusMorbillivirus genusgenus and andSeV to SeV to the Respirovirus genus. The life cycles of MV and SeV are very similar, but there are several important the Respirovirus genus. The life cycles of MV and SeV are very similar, but there are several important differences. Their attachment to host cells occurs through different cell entry receptors and different differences. Their attachment to host cells occurs through different cell entry receptors and different viral cell attachment proteins. The MV virus uses an H protein with hemagglutinin activity, while viral cell attachment proteins. The MV virus uses an H protein with hemagglutinin activity, while SeV SeV uses the HN protein with hemagglutinin (H) and neuraminidase (N) activities. In addition to usesthese the HN proteins, protein the with genomes hemagglutinin of these viruses (H) encode and neuraminidase 5 structural proteins (N) activities.and accessary In additionproteins. The tothese proteins,main the structural genomes proteins of these for both viruses viruses encode are: Nucleoprotein 5 structural proteins (N), Phosphoprotein and accessary (P), proteins. Matrix protein The main structural(M), Fusion proteins protein for both(F), and viruses Large are:Protein Nucleoprotein (L). The MV genome (N), Phosphoprotein encodes two non (P),-structural Matrix proteins, protein (M), FusionC and protein V, [20], (F), while and the Large SeV genome Protein encodes (L). The a set MV of non genome-structural encodes proteins, two collectively non-structural referred proteins, as C andC-proteins V, [20], while(C’, C, the Y1, SeVY2, V, genome W) [21]. encodes Viral replication a set of non-structural for MV and SeV proteins, follows a collectively negative-stranded referred as C-proteinsRNA virus (C’, replication C, Y1, Y2, model V, W) in [21 which]. Viral genomic replication RNA (minus for MV strand and) is SeV used follows as a template a negative-stranded to create a RNAcopy virus of replication positive sense model RNA, in employingwhich genomic the RNA RNA-dependent (minus strand) RNA polymerase is used as embedded a template in to the create a copyvirion. of positive The plus senseRNA is RNA, further employing used as a template the RNA-dependent for making multiple RNA copies polymerase of the minus embedded RNA. The in the plus RNA is also translated by the host’s ribosomes, producing all viral proteins. Viruses are then virion. The plus RNA is further used as a template for making multiple copies of the minus RNA. assembled from these proteins along with genomic RNA and budded from the host cell. Both MV and The plus RNA is also translated by the host’s ribosomes, producing all viral proteins. Viruses are then SeV can form syncytia by fusing neighboring infected and non-infected cells into a polykayion. assembled from these proteins along with genomic RNA and budded from the host cell. Both MV and SeV can form syncytia by fusing neighboring infected and non-infected cells into a polykayion. Cancers 2020, 12, 3659 4 of 28

So, two related processes can occur: Efficient intratumor virus spread and the resulting mass death of malignant cells. In general, oncolytic paramyxoviruses stimulate strong innate and adaptive anticancer immune responses by generating multiple danger signals. They are potent inducers of IFN and other immuno-stimulating cytokines, and they efficiently induce anticancer activity of natural killer cells, dendritic cells, and cytotoxic T lymphocytes [18]. Finally, the viruses require proteolytic cleavage of their fusion proteins by cellular serine proteases, which are sometimes overexpressed in cancer cells [14–16], and could add an additional level of specificity to viral oncolytic activity. Moreover, the that encodes a fusion protein in the paramyxovirus genome can be replaced with a constructed fusion protein that could be processed by tumor-associated matrix metalloproteases. The purpose of this review is to summarize and analyze information related to expression patterns of receptors for oncolytic paramyxoviruses (both natural and artificially retargeted). In current literature and existing databases, receptor expression patterns are evaluated by quantitative and semi-quantitative measurements of RNA or protein. Analysis of the collected information may ultimately aid in the development of tests to identify oncolytic viruses that are more effective against specific malignancies. To compare expression levels in normal and cancerous tissues for each studied virus receptor, we analyzed a Human Protein Atlas (HPA) database [15,16,22]. HPA accumulates protein expression information from experiments performed by HPA project participants along with RNA-Seq information from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Functional Annotation of the Mammalian Genomes (FANTOM5) project databases [16]. We also analyzed relevant literature and patterns in the PubMed database. Several paramyxovirus representatives have oncolytic properties. Among them are attenuated measles and mumps viruses, Newcastle disease virus, and SeV [17,18]. In this review, information related to MV and SeV receptors is compiled and analyzed.

2. Measles Virus as an Oncolytic Agent MV (Box1, Figure3) causes a highly contagious disease transmitted by respiratory aerosols that can trigger severe immunosuppression and even immune amnesia.

Box 1. Measles Virus (MV).

Taxonomy: The virus belongs to the genus Morbillivirus within the family Paramyxoviridae [23,24]. Host: Human Origin: Most likely MV originated from a virus of non-human species. Genome: MV has a single-stranded, negative-sense, non-segmented RNA genome that is ~16K nucleotides long. Virion: MV is an enveloped virus with a membrane. Proteins: Nucleoprotein (N), phosphoprotein (P), matrix protein (M), fusion protein (F), hemagglutinin (H), large protein (L), and two nonstructural proteins C and V. is translated from the same mRNA as the P protein but using an alternative start codon in an overlapping ORF. Protein V is translated from an edited P mRNA.

Significant efforts by virologists in the second half of the 20th century were focused on finding a safe and effective vaccine against MV. In 1954, one MV isolated strain, when passaged in cell culture, gradually lost its pathogenicity, and became attenuated. From this attenuated variant of the virus, one of the first vaccine strain (Edmonston, denoted in the following text as MV-Edm) was obtained. Further passages of MV-Edm generated the more attenuated Schwarz and Moraten strains, which are still in use for vaccination against measles [24,25]. During the 20th century clinicians reported on isolated cases where measles disease relieved or caused remission of certain malignancies. Reports include descriptions of the regression of a number of hematological malignancies that took place after MV infection (reviewed in [26]). At the end of the century, virologists and oncologists started to investigate oncolytic properties of attenuated MV strains that are incapable of causing serious infection. Cancers 2020, 12, 3659 5 of 28 Cancers 2020, 12, x 5 of 27

FigureFigure 3. 3. SchematicSchematic representation representation of ofthe the MV MV genome genome (A), (A virion), virion (B) (andB) and host host cell entry cell entry receptors receptors (C). The(C). TheRNA RNA genome genome (gRNA) (gRNA) contains contains six six transcription transcription units units that that codes codes 6 6 main main structural structural proteins proteins:: nnucleoproteinucleoprotein (N), (N), p phosphoproteinhosphoprotein (P), (P), matrix matrix protein protein (M), (M), fusion fusion protein protein (F), h (F),emagglutinin hemagglutinin (H), and (H), landarge largeprotein protein (L) RNA (L) RNA dependent dependent RNA RNA polymerase polymerase (RdRp) (RdRp).. The The viral viral genome genome also also codes codes the the nonstructuralnonstructural V V and and C C proteins proteins,, which are antagonists of host innateinnate immunity.immunity. The transcription unitsunits for for each each structural structural gene gene are are separated separated by by non non-transcribed-transcribed trinucleotide trinucleotide intergenic intergenic sequences sequences and and togethertogether are are flanked flanked by by sho shortrt leader leader and and trailer trailer sequences sequences containing containing the the genomic genomic promoter promoter (on (on the the minusminus strand) strand) and and the the antigenomic antigenomic promoter promoter (on (on the the plus strand). Inside Inside the the virion virion,, genomic genomic RNA RNA formsforms a a complex complex with with N, N, L L,, and P proteins. The The virus virus is is enveloped enveloped by by a a lipid lipid membrane membrane th thatat has has glycoproteinsglycoproteins H and FF associatedassociatedwith with it it as as virion virion surface surface proteins. proteins These. These proteins proteins coordinate coordinate how how the thevirus virus finds finds cells cells and and enters enters them. them. For For H H protein, protein three, three receptors receptors have have beenbeen identified:identified: C Complementomplement regulatoryregulatory molecule molecule CD46, CD46, the the cell cell adhesion adhesion molecule molecule nectin-4 nectin and- the4 and signaling the signaling lymphocyte lymphocyte activation activationmolecule (SLAM).molecule MV (SLAM). wild-type MV strains wild-type use SLAM strains and use nectin-4 SLAM asand cell nectin entry-4 receptors. as cell entry Vaccine receptors. strains Vaccineand a small strains fraction and a of small wild fraction type strains, of wild in type addition, strains use, in CD46 addition as a, celluse entryCD46 receptor.as a cell entry receptor.

MVMV-Edm-Edm and and its its derivativ derivativeses were were the theprimary primary strains strains tested tested as oncolytic as oncolytic agents agents[27,28]. [T27hese,28]. strainsThese can strains infect can and infect kill a and wide kill variety a wide of cancer variety cells of in cancer vitro cellsand inin vivo vitro. Theyand arein vivo currently. They being are invcurrentlyestigated being preclinically investigated and preclinicallyin clinical trials and for in clinicaltreatment trials of a for large treatment spectrum of a of large malignancies, spectrum includingof malignancies, ovarian including, breast, ovarian,head and breast, neck head cancers and, neckas well cancers, as glioblastoma, as well as glioblastoma, multiple myeloma multiple, memyeloma,sothelioma mesothelioma,, and T-cell lymphoma and T-cell [27,28] lymphoma. A virus [27, 28with]. Aoncolytic virus with properties oncolytic can properties be delivered can not be onlydelivered locally not intratumorally only locally intratumorally,, but also system butically also, systemically,including by includingintraperitoneal by intraperitoneal and intravenous and injectionintravenous routes injection. In some routes. trials In patients some trials survival patients compared survival favorably compared with favorably that of with historical that of historicalcontrols andcontrols the s andide effects the side of etheffects virotherapy of the virotherapy were mainly were mild mainly [27,28] mild. [27,28].

3. Natural MV Receptors 3. Natural MV Receptors For wild type and vaccine MV strains, the proteins CD150 (SLAM or SLAMF1) [29,30] and/or For wild type and vaccine MV strains, the proteins CD150 (SLAM or SLAMF1) [29,30] and/or nectin-4 (also called poliovirus-receptor-like 4 (PVRL4)) [31–33] function mainly as cell entry receptors. nectin-4 (also called poliovirus-receptor-like 4 (PVRL4)) [31–33] function mainly as cell entry A small fraction of wild type MV strains and all modern vaccine strains derived from the Edmonston receptors. A small fraction of wild type MV strains and all modern vaccine strains derived from the strain also use CD46 receptors (Table1, Figure3C) [34,35]. Edmonston strain also use CD46 receptors (Table 1, Figure 3C) [34,35].

Cancers 2020, 12, 3659 6 of 28

Table 1. Natural receptors for MV and their expression in normal cells.

Receptor High Expression in Normal Cells Expression Evaluation Hematopoietic stem and progenitor cells including T, B, natural killer, Multicolor flow-cytometry and dendritic cells [36–38] CD150/SLAM Immunohistochemical Spleen red pulp cells and thymus cortical tissue staining and medullary cells [14–16] AB: HPA069319,CAB002438 Immunohistochemical tissue Glandular cells of breast, stomach colon, Nectin-4/PVLR 4 staining gall bladder and others [14–16] AB: HPA016903,CAB010401 Immunohistochemical tissue Glandular cells of breast, stomach, colon CD46/membrane cofactor protein staining and others [14–16] AB: HPA010775 Abbreviations: AB: Antibodies.

RNA and protein expression patterns of MV receptors are estimated by several different approaches, including array technology, quantitative RT-PCR and RNA-Seq for RNAs, as well as immunohistochemical tissue staining, flow cytometry and western blotting for proteins. Tables1 and2 respectively summarize expression patterns of natural MV receptors described in normal and malignant cells.

Table 2. Expression of natural MV-Edm receptors in malignancies.

CD150/SLAM CD46/Membrane Cofactor Protein Nectin-4 Malignancy (Ref/Evidence) (Ref/Evidence) (Ref/Evidence) Breast cancer [39]/IS, [14–16]/IS, TCGA dataset [33,40–45]/IS, FC, PCR Cervical cancer [14–16]/IS, TCGA dataset [14–16]/IS, TCGA dataset, [14–16,33,45,46]/IS, Colorectal cancer [46]/oligo-array TCGA dataset Endometrial cancer [14–16]/IS, TCGA dataset Glioma [47] IS, FC Liver cancer [48]/PCR, IS [14–16]/IS, TCGA dataset Lung cancer [33,49]/IS, ELISA Non-small cell lung cancer [50] IS, FC [46]/Oligo-array Lymphoma [51]/PCR, IS, WB, FC [52] IS, FC Melanoma [14–16]/IS, TCGA Multiple myeloma [53]/IS, [46]/Oligo-array Ovarian cancer [54]/IS, WB [55,56]/PCR, IS, WB, FC Pancreatic cancer [57]/IS Prostate cancer [14–16]/IS, TCGA dataset Stomach cancer Thyroid cancer [14–16]/IS, TCGA dataset Urothelial cancer [14–16]/IS, TCGA dataset Abbreviations: IS: Immunohistochemical staining; FC: Flow Cytometry; PCR: Quantitative RT-PCR; TCGA: Tissue Cancer Genome Atlas; WB: Western immunoblotting.

CD150 (also called signaling lymphocytic activation molecule 1 (SLAM or SLAMF1)) is a transmembrane member of the signaling lymphocytic activation molecule family. It modulates the activation and differentiation of a wide variety of immune cells and is involved in the regulation of both innate and adaptive immune responses [36,58–60]. CD150 is expressed on the surface of hematopoietic stem and progenitor cells including natural killer cells, dendritic cells, and memory B and T cells [36–38] (Table1). Therefore, wild-type MV can infect various cells that are involved in the host’s immune response, resulting in strong immunosuppressive effects and erasure of immune memory from previous pathogen infections, causing immune amnesia [61,62]. In Japan, a set of MV-based oncolytic constructs was produced by removing MV’s ability to interact with CD150 [63–65]. The removal of interaction ability between a virus and its receptor is called “blinding”. It has been demonstrated that “blinding” results in the pathogenicity loss of the constructs, Cancers 2020, 12, 3659 7 of 28 effectively making the MV strains non-infective to monkeys [66]. However, the constructs maintain the ability to kill malignant cells, including tumors, in model animals [63–65]. Three types of human malignancies were tested as murine xenografts, including breast, pancreatic, and lung carcinomas. The animals treated with intratumoral injections of the experimental constructs survived longer (Table3).

Table 3. Retargeting MV receptors by blinding to CD150.

Model and Type Cell Type or Blinding to Effect of Virus Delivery Reference Malignancy to Animals Viability of CD150-positive lymphoid cells unaffected; reduced infection of Xenografts; Breast carcinoma [63] CD46-positive primary normal human IT virus delivery CD150/SLAM, cells; tumor stabilized or regressed no natural CD46 Pancreatic Tumor stabilized; Xenografts; [64] carcinomas animal survival prolonged IT virus delivery Lung carcinoma [65]

Nevertheless, some malignancies do overexpress CD150. Many cell lines generated from Hodgkin’s and Burkitt’s lymphomas are characterized by very high levels of CD150 mRNA and proteins [51]. Both types of lymphomas can sometimes regress after natural infection with wild-type MV (reviewed in [26]). It is likely that these malignancies could be successfully targeted by an oncolytic virus that interacts with CD150 as a cell entry receptor. This hypothesis is supported by observations that MV-Edm can infect metastases and primary tumors in mantle cell lymphoma murine xenografts [67]. Perhaps other cancers that express high levels of CD150 could also be successfully targeted by attenuated MV with the ability to interact with CD150. CD46 (complement regulatory protein or membrane cofactor protein) is a membrane glycoprotein that serves as a regulator of the complement system. By inhibiting complement activation in host cells, this protein protects cells from complement associated damage [68]. CD46 is also involved in other processes: It interacts with at least seven human pathogens and regulates the adaptive immune response by inducing differentiation of T cells into regulatory T cells [69,70]. According to HPA, CD46 protein is expressed at comparatively high levels in glandular cells of the breast, stomach, and colon as well as in several other cell types. At low levels it is expressed in almost all human cells and tissues [14–16]. CD46 expression protects a cell from complement-dependent cytotoxicity, so expression in a cancer cell promotes escape from immune surveillance and provides the cancer cell with a strong survival advantage [71]. Therefore, advanced cancers are frequently characterized by high levels of CD46 (Table2). Two studies demonstrate that e fficiency of cellular virus entry into and killing of tumor cells correlates with CD46 cell surface protein expression [52,72]. The cell vulnerability to virus infection and syncytia formation has been shown to correlate with the level of CD46 expression. Thus, at a low expression level of CD46, which is typical of normal cells, infection occurs, but intercellular fusion is negligible. However, tumor cells with a higher CD46 expression are much more vulnerable to virus infection along with the formation of syncytia [72]. Based on these observations, CD46 could be included in a list of biomarkers to predict potential tumor response to virotherapy by attenuated MV. Nectin-4 (also called PVRL4—Poliovirus-Receptor-Like 4) is a transmembrane protein that belongs to a family of Ca2+-independent immunoglobulin-like cell adhesion molecules. It contributes to cell to cell adhesion and intercellular communication [73,74] and serves as a receptor for MV (Table1, Figure3A). According to HPA, the nectin-4 protein is expressed at high or medium levels in glandular cells of breast, colon, gall bladder, and stomach as well as in some other cells and tissues [14–16]. Nectin-4 gene expression promotes malignant cells’ evasion of growth constraints related to matrix detachment. This gene has been frequently found to be amplified and overexpressed in some solid tumors [75,76]. A summary of malignancies in which nectin-4 has high expression levels is Cancers 2020, 12, 3659 8 of 28 presented in Table2. Most likely, this protein helps MV-Edm to enter a malignant cell. The observation that nectin-4 was specifically used for MV entry into nectin-4 positive cancerous breast and colon cells supports this hypothesis [45]. Therefore, nectin-4 is another candidate to be included in a list of sensitivity biomarkers for oncolytic attenuated MV.

4. MV Retargeting for Binding New Cancer-Associated Proteins Cellular entry of MV-Edm requires the interaction between viral H protein and cell surface receptors. In many types of normal cells, expression of CD150, CD46, or nectin-4 is detected. To make the oncolytic virus safer by targeting cancer cells more specifically, it would be beneficial to modify the virus preference for host cell entry. By changing viral H protein, which is responsible for the virus–receptor interaction, MV-Edm can be retargeted to infect different cells. The affinity of the receptor for the virus is an important determinant of infectivity and, consequently, infection-induced cell fusion. In this context, affinity is a measure of the strength with which a virus binds to a cellular receptor. The fusion of infected cells with each other depends on this affinity and on the density of receptors on the cell surface, which is a measure of the concentration of receptors in the cell membrane. This density depends on the levels of intracellular expression of the receptor that can be measured. There is a threshold for receptor expression below which cell fusion is ineffective. There is also another threshold for receptor expression, above which there is no further increase in membrane fusion in cell culture [77,78]. Because of this non-linear relationship between viral infection-induced cell fusion and the level of expression of the receptor in vivo, it is very important to test any retargeting strategy. Retargeting can be achieved by inserting genes that encode single-chain fragments of antibodies or other receptor-binding ligands into the viral genome (Figure3A). This genetic engineering procedure allows for the creation of MV constructs that target a wide range of cancer associated proteins. Several studies describe such virus retargeting modifications (Table4). The retargeting is a result of genomic changes that enable MV to use different cancer cell associated proteins as cell entry receptors (Table4).

Table 4. Retargeting MV for binding to new receptors.

Model and Type of Introducing Cell Type or Blinding to Effect Virus Delivery to Reference Property to Bind Malignancy Animals Via fusion of viral H protein with epidermal growth factor (EGF) or insulin-like growth factor 1 (IGF1) receptor binding domains Infection of EGF or IGF1 EGF or IGF1 EGF or IGF1 receptor positive and receptor positive Cell culture [79] receptors CD46 negative cells cells Via fusion of viral H protein with a single-chain variable fragment (scFv) Carcino-embryonic Infection of CEA CEA-positive cells Cell culture [80] None antigen (CEA) positive cells Xenografts; CD20 Delayed growth Fibrosarcoma [81] IP virus delivery Malignant cells less Xenografts; tumorigenic, construct premixed CD38 Multiple myeloma [82] animal survival with tumor cells prolonged before implantation Via fusion of viral H protein with echistatin, which is a 49-residue peptide from family of disintegrins Integrin Tumor regressed or Xenografts; Multiple myeloma [83] alpha(v)beta3 stabilized IT virus delivery Cancers 2020, 12, 3659 9 of 28

A proof of the possibility of redirection of MV cell targeting was obtained with engineered MV-Edm based constructs targeting three cancer associated proteins: EGF, IGF1 [79], and (CEA) [80]. In cell cultures, MV-Edm constructs can successfully target, infect, and destroy corresponding malignant cells that overexpress one of these three proteins. The retargeting genetic engineering approach was further used for creation of viral constructs with ability to recognize two other membrane associated proteins. One was phosphoprotein CD20 [81], which is expressed in normal hematopoietic cells and overexpressed in B-cell lymphomas, leukemias and some other malignancies (Table5). Another was glycoprotein CD38 [ 82], expression of which characterizes immune cells and overexpression characterizes NK/T-cell lymphomas, lymphocytic leukemias, multiple myelomas and other malignancies (Table5). Antitumor e ffects of both constructs were tested in animal xenografts. Implanted CD20-positive fibrosarcomas demonstrated delayed growth after IP construct delivery, while CD38-positive multiple myeloma cells became less tumorigenic after premixing with the corresponding viral construct.

Table 5. Expression of retargeted measles virus receptors in normal and malignant cells.

Expression Receptor Name Alternative Name In Malignancies In Normal Cells and Tissues Different subfamily members Carcinoembryonic High or moderate in gastric, expressed to different degrees CEA antigen-related cell colorectal, lung ovarian, breast, in hematopoietic cells, glyco-proteins adhesion molecules and cervical cancers [84] glandular cells of colon, etc. [14–16] High in leukemias [85], gliomas [86,87], colorectal, High in glandular cells of gall prostate, endometrial, bladder, endometrium, cervix pancreatic and thyroid and uterus [14–16]. cancers [14–16], and non-small Also expressed on the surfaces CD133 Prominin-1 (PROM1) cell lung cancers [88]. of hematopoietic stem Levels in gliomas [87] and cells [89], epithelial progenitor non-small cell lung cancers [88] cells [90], and neural and glial are negatively correlated with stem cells [86] patient survival [87] Frequently high in B-cell Low and moderate expression lymphomas [91], B-cell MS4A1, B1, Bp35, CVID5, in white and red pulp in leukemias [92], and melanoma LEU-16, MS4A2, S7, spleen, hematopoietic cells of CD20 stem cells [93]. Less frequent membrane spanning bone marrow, lymphoid in Hodgkin’s lymphoma [94], 4-domains A1 tissues of appendix. and myeloma [95], other tissues [14–16] and thymoma [96] High in chronic lymphocytic High in large spectrum of Cyclic ADP ribose leukemia [97,98] immune cells as well as CD38 hydrolase in NK/T-cell lymphomas [99], glandular cells of prostate and and in multiple myeloma [100] seminal vesicles [14–16] Particular high in gliomas, Low levels in a number of Epidermal growth factor high in renal, urothelial, lung, normal tissues but high levels ErbB 1, HER1 receptor 1 (EGFR1) liver, and many in trophoblastic cells of other cancers [14–16] placenta [14–16] Frequently highly overexpressed in malignancies Medium levels in glandular Receptor including breast [101], cells of appendix, breast, Epidermal growth factor tyrosine-protein kinase, stomach [102], and cervix, myocytes, receptor 2 (EGFR2) ErbB-2, HER2/neu, endometrial [103,104], ovarian, respiratory epithelium, ERBB2, CD340 uterine [105] colorectal [106], and urothelial cells [14–16] thyroid [107], urothelial [108] Cancers 2020, 12, 3659 10 of 28

Table 5. Cont.

Expression Receptor Name Alternative Name In Malignancies In Normal Cells and Tissues Low level of expression in High in lymphomas, thyroid, bone marrow hematopoietic Insulin-like growth IGF-1 receptor liver, pancreatic, and many cells, respiratory cells, and factor receptor (IGF1R) other cancers [14–16] glandular cells of gallbladder [14–16] High in ovarian Folate receptor alpha, cancers [14–16]; particularly Glutamate Medium levels in brain, lung, Folate receptor 1 strong and frequent expression carboxypeptidase II and salivary gland (FOLR1) of mRNA observed in (GCPII), and folate tissues [14–16] non-mucinous ovarian hydrolase 1 cancers [109] Prostate specific High expression in malignant High expression in prostate membrane antigen, prostate cells [110] tissues [110] (PSMA) High in bone marrow, lymphoid tissues, neutrophils, UPA, UPAR, CD87, Infrequently expressed in and respiratory epithelial cells PLAUR malignant cells [14–16] of the nasopharynx and bronchus

An alternative approach for MV-Edm retargeting to cell surface antigens of choice was developed by using cystine knot proteins instead of single chain antibodies [83,111]. These short proteins are capable of binding integrins, which are frequently overexpressed by a tumor’s vascular endothelium. The retargeted virus was able to infect and kill cancer cells that expressed the integrins, including glioblastoma, medulloblastoma, melanoma and others [111]. Most importantly, when injected intravenously into animals carrying glioblastoma, the construct reached the tumor and caused cytopathic effects [111]. The introduction of the ability to bind new viral receptors may be accompanied by blinding to the natural receptors CD150 and CD46. This blinding reduces the potential infection of CD150- and CD46-positive normal cells because CD150 is expressed on the surface of normal hematopoietic stem and progenitor cells [36–38], while high CD46 expression characterizes glandular cells of many organs [14–16]. Blinding increases the safety of viral construct application because MV infection is usually detrimental to host healthy cells. Blinding to specific receptors became possible after identification of residues in H protein that are necessary for CD150 or CD46 binding [112]. Multiple retargeting strategies have been used to modify the MV-Edm genome. These include the genomic introduction of genes encoding single-chain antibody fragments (scFv), cystine knot proteins, and designed ankyrin repeat proteins (DARPins). The antibody fragment strategy allowed the targeting of various cancer associated proteins such as CD38, epidermal growth factor receptor 1 [113,114], folate receptor 1 [109], prostate specific membrane antigen [110], human epidermal growth factor receptor 2 (HER2/neu) [77], prominin or CD133 [115,116], and plasminogen activator urokinase receptor [117,118]. The cystine knot strategy targeted integrins, which are highly expressed in glioblastomas, medulloblastomas and melanomas [111]. Finally, the DARPin strategy targeted ovarian carcinomas that express HER2/neu or/and epithelial cell adhesion molecule (EpCAM) [119,120], along with EGFR-expressing glioblastomas [121]. To reduce bystander killing of receptor-expressing normal cells, a gene that encodes an engineered viral fusion protein and that can be processed by tumor-associated matrix metalloproteases was added to the virus genome. This introduction made the targeting of the virus to tumor cells very specific [121]. All of these new constructs were tested in cell lines and some in xenograft models of human malignancies, and demonstrated strong or moderate antitumor effects (Table6). Cancers 2020, 12, 3659 11 of 28

Table 6. MV receptor blinding and retargeting.

Model; Route Introducing Cell Type or of Virus Blinding to Effect Reference Property to Bind Malignancy Delivery to Animals Via fusion of viral H protein with scFv Tumor stabilized; CD38 or EGFR Xenografts; IT CD38 or EGFR animal survival [113,114] positive cancers or IV prolonged Biodistribution more specific towards Folate receptor 1 malignant tissues; Ovarian cancer Xenografts; IV [109] (FOLR1) tumor stabilized; animal survival prolonged Prostate specific Tumor stabilized; membrane antigen, animal survival Prostate cancer Xenografts; IT [122] (PSMA) prolonged Malignant cells infected in vitro, HER2 protein tumor regressed, Ovarian cancer Xenografts; IP [77,78] animal survival prolonged CD150/SLAM Glioblastoma, lung and CD46 Tumor formation metastases of colon CD133, Prominin1 Xenografts; IT inhibited; animal cancer and [115,116] (PROM1) or IV survival prolonged hepatocellular carcinoma Delayed development of lung Syngeneic and Urokinase receptor Breast cancer [117,118] metastases, animal xenografts; IV survival prolonged Via fusion of viral H protein with cystine knot proteins Malignant cells Glioblastoma, killed in vitro; Glioblastoma Integrins medullo-blastoma, [111] cytopathic effects xenografts; IV melanoma produced in vivo Via fusion of viral H protein with designed ankyrin repeat proteins (DARPin) Animal survival Bispecific binding significantly to HER2/neu, Ovarian cancer Xenografts; IT [119,120] prolonged, tumor and/or EpCAM burden reduced Malignant cells Glioblastoma EGFR Cell lines [121] killed in vitro multiforme

5. SeV as an Oncolytic Agent SeV causes respiratory infections in mice and other rodents (Box2). However, it is not associated with any human disease and can be a safe oncolytic agent. Safety of SeV for humans, including small children, has been confirmed experimentally. The virus in the form of nasal drops has been tested as a vaccine against human parainfluenza virus type 1 (HPIV-1), which causes respiratory symptoms in humans. Testing in adults and children demonstrated that experimental administration of wild type SeV triggered production of neutralizing antibodies towards HPIV-1 and was well tolerated [123,124]. Replication competent SeV vector showed an excellent safety profile in a stage 1 clinical trial [125] and is considered highly suitable as an antigen delivery tool [126,127]. Pre-existing anti-vector immunity didn’t affect the immunogenicity of SeV-delivered antigens [126]. Cancers 2020, 12, 3659 12 of 28

Box 2. Sendai Virus (SeV).

Taxonomy: The virus belongs to the genus Respirovirus within the family Paramyxoviridae [23]. Host: The virus causes respiratory infections in mice, hamsters, guinea pigs, rats, and other rodents [128]. Genome: SeV has single-stranded, negative-sense, non-segmented RNA genome that is ~15K nucleotides long [129]. Virion: SeV is an enveloped virus with a lipid membrane. Proteins: Nucleoprotein (N), phosphoprotein (P), matrix protein (M), fusion protein (F), hemagglutinin- neuraminidase (HN), large protein (L), and nonstructural proteins collectively referred as C-proteins (C’, C, Y1, Y2, V, W) that are translated from an alternative RNA transcript of the P gene [129].

Wild-type SeV can replicate and productively infect a large spectrum of malignant cells ex vivo (Table7). A pilot study demonstrated that some canine mastocytomas can be eradicated with the help of SeV injections [130]. However, the virus is infectious and immunosuppressive for laboratory rodents. Therefore, for studying SeV oncolytic properties in a rodent model, a set of viral constructs that are nonpathogenic for experimental mice was created. These constructs were tested in animals bearing a variety of human xenograft tumors including sarcoma, melanoma, pancreas, colon, hepatocellular and prostate carcinomas. The SeV constructs promoted growth suppression or even complete tumor eradication of these malignancies [131–134], and elimination of established brain tumors [135]. In addition, UV- inactivated SeV virions have immune-stimulating properties: In syngeneic mice they promote immunomodulated tumor regression of colon [136,137], bladder [138], and kidney [139] cancers. In murine xenografts these virions contribute to the eradication of human prostate cancer [140].

Table 7. Cancer cell-lines susceptible to SeV infection.

Cell Line Type of Malignancy Reference Human origin MCF7 Breast carcinoma [141] HeLa Cervical carcinoma [142] CaCo2 Colon carcinoma [13] U118 Glioblastoma [143] U87MG Most likely, human glioma [144] Hep G2 [142,145,146] Hepatic carcinoma Huh7 [146,147] A549 [142,148–150] Lung carcinoma Calu-3 [13] U937 Histiocytic lymphoma [149] Namalwa Burkitt’s lymphoma [149,151] PC-3 Prostate carcinoma derived from metastatic site in bone [152] DU145 Prostate carcinoma derived from metastatic site in brain Murine origin 4T1 Mammary gland metastatic adenocarcinoma [142]

So far, SeV has not been widely tested in clinical settings. An attempt to treat one case of human leukemia with a set of viruses, including SeV, was undertaken in 1964 at the Clinical Research Center of University Hospitals of Cleveland. Short-term remission in one patient affected by acute leukemia was observed after IV virus injection [153]. A few patients affected by various malignancies were treated with intradermally or intratumorally injected SeV in Moscow (Russia) in the 1990s. In a small fraction Cancers 2020, 12, 3659 13 of 28 of patients treated with the virus, primary tumors and metastases disappeared, even when virotherapy was a monotherapy. These patients experienced a pronounced long-term remission that sometimes lasted more than 5–10 years [154].

6. SeV receptors SeV, as a representative of respiratory viruses, uses mainly molecules containing sialic acid residues (sialylated proteins as well as lipids) as cell entry receptors. Thus, bovine (GP2) [155], human asialoglycoprotein receptor (ASGR1) [145,156], and sialoglycoprotein ( A (GYPA)) [157] bind SeV with high affinity and could act as virus receptors. Glycans (polysaccharides) attached to lipids could also bind SeV and serve as entry receptors. For example, two carbohydrates, sialyl Lewis-x and VIM-2, when attached to lipids, are capable of binding to SeV with high affinity [158]. Other SeV receptors are represented by gangliosides (Table8, Figure4).

Table 8. Cell entry receptors for sendai virus.

Expression in Sub-Type of Affinity to Function in Normal Receptor Ref. Normal Human Molecule SeV Human Cells Cells Glycoproteins Removes the target Human glycoproteins from asialoglyco-protein ASGR1 High [145,156] Hepatocytes [14–16] circulation in the receptor 1 liver Bovine Glycoprotein2/GP2 High [155]- glycoprotein 2 Defines the antigenic Bone marrow, Human Glycophorin High [157] determinants for immune cells, sialo-glycoprotein A/GYPA/CD235a some blood groups [14–16] Fucosylated glycans Serves as a blood Sialyl Lewis-x group antigen and Bone marrow, Tetra-saccharide antigen participates in erythrocytes [14–16] (sLeX/CD15s) cell-cell recognition High [158] process. - VIM-2 antigen Granulocytes and Unknown dodeca-saccharide (CD65s) monocytes [158] Sialylated gangliosides Cell-cell recognition, Granulocytes, GD1a, GT1b, and Not reported [159] adhesion, and signal normal myeloid cells GQ1b, transduction [160] Many cell types, but Ganglio-series mainly the cells of GT1a, GP1c High [161–163]- the nervous system [164] GD1a, GT1b Moderate [161–163]- GQ1b Very high GM3 Low [165] Cell–cell recognition Blood cells, liver Sialosylparagloboside Common for (SPG, Very high [163,166]- non-neural cells NeuAcα2-3PG) NeuAcα2-3I [165]- Neolacto-series NeuAcα2-3i NeuGca2-3I NeuAca2-6PG Moderate - NeuAca2-6I Cancers 2020, 12, 3659 14 of 28

Cancers 2020, 12, x 14 of 27

Figure 4. SeVFigure receptors. 4. SeV receptors. The namesThe names of of receptors receptors with known known high high binding binding affinity a toffi thenity virus to theare virus are marked with stars. The names of receptors that are overexpressed in some malignancies are in bold marked withand stars.underlined. The names of receptors that are overexpressed in some malignancies are in bold and underlined. Sialyl-Lewis X antigen (sLeX), also called stage-specific embryonic antigen 1 or cluster of Sialyl-Lewisdifferentiation X antigen 15 (CD15s) (sLeX),, is one of also the most called important stage-specific blood group embryonic antigens. It is antigena tetrasaccharide 1 or cluster of differentiationand may 15 be (CD15s), attached isto onea lipid of or the a protein most [92 important–94]. SLeX blooddemonstrated group high antigens. binding affinity It is a tetrasaccharideto SeV when attached to [158]. However, whether sLeX can bind with a virus when attached and may beto a attached protein isto unknown. a lipid orExpression a protein of sLeX [92– correlates94]. SLeX significantly demonstrated with malignant high binding cell invasion, affinity to SeV when attachedtumor to recurrence sphingolipid and overall [158 patient]. However, survival whether for an extremely sLeX can broad bind range with of cancers a virus (Table when 9) attached to a protein(reviewed is unknown. in [167]). It Expression is likely that sLeX of sLeX positive correlates cancer cells significantly use the leukocyte with adhesion malignant pathway cell for invasion, tumor recurrenceextravasation, and which overall facilitates patient tumor survival invasion for and an spread. extremely Tumors broadwith high range expression of cancers of this (Table9) antigen can bind SeV and are potential candidates for SeV therapy. (reviewed in [167]). It is likely that sLeX positive cancer cells use the leukocyte adhesion pathway for extravasation, which facilitatesTable 9. Receptors tumor for invasion SeV and their and exp spread.ression in malignancies. Tumors with high expression of this antigen can bind SeV and are potential candidates for SeV therapy. Monoclonal Receptor Malignancy/Effect of Receptor Expression Ref. AB Table 9. Receptors for SeV and their expression in malignancies. Availability Human High expression in liver cancer and occasionally moderate asialoglyco- Two variants expression in gliomas, renal, pancreatic, colorectal, and ovarian [14–16] Monoclonal AB Receptorprotein Malignancy/Effect of Receptor Expression Ref. [14–16] cancers Availability receptor 1 Human NonHigh-small expression cell lungin cancer/enhances liver cancer and post occasionally-operative recurrence [168,169] asialoglyco-protein Lungmoderate cancer, expression distant metastases in gliomas, renal, pancreatic, [14–16[171]] Two variants [14–16] receptor 1 Colorectalcolorectal, cancer/promotes and ovarian cancers liver metastases, decreases time of [172–174] Sialyl-Lewisx diseaseNon-small-free survival cell lung cancer/enhances post-operative Many [168,169] Antigen Gastricrecurrence cancers/decreases patient survival time [175,176] variants (sLeX/CD15) Breast cancer/decreases patient survival time [177–179] [170] ProstateLung cancer, tumor/promotes distant metastases bone metastases [171] [180–182] CellColorectal lines of var canceriable/promotes origin/high liver expression metastases, enhances decreases adhesion of [172–174[183]] malignanttime of disease-free cells to vascular survival endothelium Gastric cancers/decreases patient survival time [175,176] Sialyl-Lewisx Breast cancer/decreases patient survival time [177–179] Many variants [170] Antigen (sLeX/CD15) Prostate tumor/promotes bone metastases [180–182] Cell lines of variable origin/high expression enhances [183] adhesion of malignant cells to vascular endothelium Variable cancers/high expression related to lymphatic invasion, venous invasion, T stage, N stage, M stage, Review [167] tumor stage, recurrence, and overall patient survival Cancers 2020, 12, 3659 15 of 28

Table 9. Cont.

Monoclonal AB Receptor Malignancy/Effect of Receptor Expression Ref. Availability VIM-2 antigen Acute myeloblastic leukemias [160,184,185] One variant [170] (CD65s) Breast cancer stem cells [186] GD1a Many variants [170] Castration-resistant prostate cancer cells [187] Brain metastases from colon, renal, lung, esophagus, GT1b [188] Three variants [170] pancreas, and mammary carcinomas Castration-resistant prostate cancer cells [187] SPG One variant [189] Lymphoid leukemia cells [189,190]

VIM-2 antigen, (also called cluster of differentiation 65 sialylated [CD65s]), is a carbohydrate that can be attached to a sphingolipid and has high binding affinity to SeV [158]. VIM-2 is expressed on surfaces of granulocytes, normal myeloid cells, and cells of acute myeloblastic leukemias [160,184]. Its expression is critically important for extravascular infiltration of acute myeloid leukemia cells [185]. Perhaps myeloblastic leukemias that are resistant to modern therapies could be treated with SeV. Gangliosides are sialic acid-containing that are capable of binding SeV. It has been demonstrated that these molecules can serve as SeV cell entry receptors (Table7). There is substantial evidence that at least three of them, SPG, GD1a, and GT1b, are highly involved in carcinogenesis and metastasis (Table8). High expression of SPG characterizes lymphoid leukemia cells [189,190] and GD1a characterizes breast cancer stem cells [186]. High expression of both SPG and GD1a was found in castration-resistant prostate cancer cells [187]. High expression of GT1b is universally associated with brain metastases that originate from an extremely broad spectrum of cancers [188]. GM3, GD1a, and GT1b expression in a cell might be less predictive of SeV infectability than the expression of other molecules (104). Therefore, sLeX, VIM-2 and SPG are potential biomarkers for identification of cancers that could be efficiently infected by the virus. However, it is likely that new receptors for the SeV virus will be identified in the future. Cellular expression of gangliosides is currently evaluated using -specific antibody-based methods. These methods are not always suitable for large-scale screenings. Moreover, anti- monoclonal antibodies are not always commercially available [170]. Therefore, indirect measurement of ganglioside expression through expression levels of fucosyltransferases and glycosyltransferases, which are enzymes that finalize ganglioside synthesis, represents an alternative. Expression of these enzymes and production of gangliosides are highly correlated [187]. At least five representatives of the fucosyltransferase family and six representatives of the glycosyltransferase family are responsible for synthesis of gangliosides that could serve as SeV receptors (Table S1). All these proteins are frequently overexpressed in various tumors and their expression levels correlate with tumor metastatic status and duration of patient survival (Table S2). These enzymes deserve to be studied as potential biomarkers of the oncolytic infectivity of SeV.

7. Potential Problems of Virus Delivery and Retargeting

7.1. Preexisting Immunity One potential problem of MV and SeV applications as oncolytic agents is pre-existing antiviral immunity, which might affect systemic tumor-targeted viral delivery and intratumoral infection spread. For MV, this immunity is a result of childhood vaccination or measles disease. For SeV, previous infection with human parainfluenza virus type 1 (HPIV1) causes this immunity to the extent that the two viruses share some antigenic determinants [123,124]. It has been shown for SeV [191] and for MV [192] that prevalence of specific neutralizing antibodies against these viruses in adult human Cancers 2020, 12, 3659 16 of 28 population is extremely variable. It is still largely unknown to what degree preexisting immunity may decrease the effect of oncolytic virotherapy. However, some virus delivery approaches discussed in the next section might help minimize this problem.

7.2. Virus Transportation and Tumor Delivery Oncolytic virus constructs can be preloaded to specific cell carriers ex vivo and subsequently, after intravenous injection, transported to tumor sites in vivo [193,194]. Hypothetically, dendritic cells (DCs) could serve as oncolytic virus transportation vehicles. These cells can be infected by both vaccine and wild type strains of MV [195] via the CD150 cell receptor [196]. MV-infected DCs have higher motility toward the epithelial cell layer compared to uninfected ones. Therefore, MV infection enables rapid trafficking of the virus toward epithelial cells [197] and, perhaps, to other tissues including malignant tumors and metastases. Blinding of MV constructs to CD150 increases virus safety but might decrease efficiency of virus tumor delivery through its natural cell carriers such as DCs. SeV can also infect DCs [198] and can transform them into activated mature cells that efficiently contribute to tumor clearance and animal survival [199]. It is not known if MV-Edm or SeV-loaded DCs could ensure viral antibody protection and efficient tumor delivery; however, it is likely. Researchers should not ignore this hypothetical natural route of virus delivery to the tumor. For example, reovirus-loaded DCs protect the virus from neutralizing antibodies and facilitate viral infection of transplanted melanoma cells in model animals [200,201]. The ability of DCs to migrate after viral infection may facilitate viral tumor delivery without detection by host pre-existing immunity. Consequently, this ability might be a great asset for oncolytic virotherapy.

8. Additional Factors Determining Cell Sensitivity to Viruses The presence of viral receptors is a necessary but not sufficient condition for a cell to be vulnerable to viral infection. Despite the presence of the receptors, a malignant cell can be resistant to the virus when the functioning of the IFN pathway is not impaired [202]. If the pathway is active in the cancer cell and the IFN signal is transduced from the cell surface to its nucleus, the cell can be protected from viral infection. The cells’ ability to activate constitutively expressed genes of the IFN response pathway (ISGs) was the main prognostic factor for detection of carcinomas resistant to MV-Edm. Virus resistance of ovarian carcinomas and gliomas was linked to characteristic expression patterns of 22 ISGs [28]. Similar results were obtained for other malignancies; the sensitivity of melanoma cells to attenuated MV was associated with their response to type I IFN, even though MV receptor levels were the same among the tested cells [203]. The absence of certain proteases is another reason for the inability of the host cell to produce infectious virus. Expression of type II transmembrane serine proteases (TTSPs) by a cell is critical for the proteolytic activation of paramyxovirus F-proteins. Furin serves as an F-protein activating protease for MV [6] while other proteases such as PSB2 [7–9], PRSS1 [10], PLG [11], F10 [12], and TMPRSS2 [13]) serve a similar function for SeV. A host cell that does not express high enough levels of TTSPs can produce only noninfectious virions, rather than infectious virus particles. Expression patterns of TTSPs are variable among malignant cells and some cancers’ progression has been shown to relate to alteration of these patterns [204]. Therefore, in some cancer cells that express paramyxovirus F-protein activating TTSPs, the virus can undergo multiple rounds of infection, whereas in other cells which do not express these proteases, the virus can undergo only one, if any, rounds of infection. In addition to those listed above, there are probably many more genes and proteins that affect the vulnerability of cancer cells to viral infection. Therefore, more research is needed to determine the target tumor cell pathways responsible for productive viral replication, post-replication processing, assembly, and budding of virions. Cancers 2020, 12, 3659 17 of 28

9. Conclusions The cell entry receptors of oncolytic paramyxoviruses are represented by different types of molecules such as proteins and glycans. The molecules that serve as viral receptors for attenuated MV and SeV have extremely variable expression patterns in malignancies. A reliable predictive model for categorization of tumor cells according to their susceptibility to oncolytic virus infection requires many input parameters, which include but are not limited to expression patterns of viral receptors. Most likely, gene signatures of several immune-related genes such as IRGs and certain type II transmembrane serine proteases may serve as useful input parameters for predictive models. The creation and verification of a multi-parameter predictive model should have measurable therapeutic benefits for oncolytic virotherapy.

Supplementary Materials: The following are available online at http://www.mdpi.com/2072-6694/12/12/3659/s1, Table S1: Processing transferases for Sendai virus receptors; Table S2: Overexpression of processing transferases for Sendai virus receptors in malignancies. Funding: This work was supported by the Intramural Research Programs of the National Library of Medicine (S.A.S.). Acknowledgments: We thank Peter Chumakov for suggesting the topic for this review and Judith Miller and Timofey Spiridonov for careful reading of this manuscript and numerous constructive suggestions. Conflicts of Interest: The authors declare no conflict of interest. Olga V. Matveeva belong to a company (Sendai Viralytics LLC). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Abbreviations

CEA Carcinoembryonic antigen EGF Epidermal growth factor EGFR Epidermal growth factor receptor FOLR1 Folate receptor 1 HER2/neu Tyrosine-protein kinase erbB-2 (human epidermal growth factor receptor 2) IFN Interferon IP Intraperitoneal delivery IT Intratumoral delivery IV Intravenous delivery MV Measles virus PVRL4 Poliovirus-receptor-like 4, molecule (nectin-4) SeV Sendai virus SLAM/SLAMF1/CD150 Signaling lymphocytic activation molecule 1 SPG Sialosylparagloboside

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